ABSTRACT The goal of our research program is to dissect the mechanisms underlying the establishment and activity of cis-regulatory elements and their control of transcriptional gene networks. We are focused on the cellular response to DNA damage, a well-conserved pathway required for preservation of genome fidelity and overall organismal homeostasis. During this funding period, we will focus on the activity of the transcription factor p53, which acts a central hub within the DNA damage gene regulatory network. Misregulation of p53 activity is directly implicated in numerous human diseases, but we lack key insight into how p53 controls cell fate decisions after exposure to DNA damage. We have generated a set of novel hypotheses regarding how cis- regulatory elements, combinatorial transcription factor activity, and 3D genome structure work in concert with p53 to maintain genome fidelity. Our group utilizes advanced genetic, epigenetic, and genomic engineering combined with classical genetic and biochemical models to parse the mechanistic contributions of regulatory elements, chromatin structure, and transcription factor activity to DNA damage response transcription and ultimately, cell fate determination. Mapping functional networks and mechanisms controlling the DNA damage response will significantly broaden our understanding of human development, aging, and build towards precise molecular control over therapeutic cellular reprogramming paradigms and genome editing.